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Background: Peripheral nerve injuries (PNIs) are common, with complex defects posing a significant reconstructive challenge. Although vascularised (VNGs) and non-vascularised nerve grafts (NVNGs) are established treatment options, there is no comprehensive summary of the evidence supporting their clinical, electrophysiological, and histological outcomes. This review aims to systematically evaluate the clinical and laboratory literature comparing VNGs and NVNGs to inform future clinical practice and research., Methods: This review was prospectively registered and reported according to PRISMA guidelines. PubMed, EMBASE, SCOPUS, and the Cochrane Register were systematically searched. Studies comparing VNGs and NVNGs in PNIs were included. Meta-analyses were performed for outcomes reported in ≥3 laboratory studies. Functional outcomes were synthesised by vote-counting based on direction of effect for clinical studies. Risk-of-bias was assessed using RoB2, ROBINS-I, and SYRCLE, and the certainty of evidence was evaluated using GRADE., Results: Seven clinical and 34 laboratory studies were included. Of the clinical comparisons, 90% and 56% identified an effect on recovery of sensibility (p = 0.01) and motor function (p = 0.05), respectively, that favoured VNGs. Nine (of 13) separate meta-analyses of laboratory studies demonstrated reduced muscular atrophy, superior axonal regeneration, and remyelination in VNGs. VNGs eliminated the 3-day interval of ischaemia otherwise sustained by NVNGs. Overall, the quality of evidence was low., Conclusion: This systematic review indicates that VNGs may offer some advantages over NVNGs in PNI reconstruction. However, due to the low quality of evidence, significant statistical heterogeneity, and clinical diversity of the included studies, these conclusions should be interpreted with caution. Further high-quality clinical trials are necessary to validate these findings., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Peripheral nerves undergo physiological and non-physiological stretch during development, normal joint movement, injury, and more recently while undergoing surgical repair. Understanding the biomechanical response of peripheral nerves to stretch is critical to the understanding of their response to different loading conditions and thus, to optimizing treatment strategies and surgical interventions. This protocol describes in detail the calibration process of the stereo-imaging camera system via direct linear transformation and the tracking of the three-dimensional in-situ tissue displacement of peripheral nerves during stretch, obtained from three-dimensional coordinates of the video files captured by the calibrated stereo-imaging camera system. From the obtained three-dimensional coordinates, the nerve length, change in the nerve length, and percent strain with respect to time can be calculated for a stretched peripheral nerve. Using a stereo-imaging camera system provides a non-invasive method for capturing three-dimensional displacements of peripheral nerves when stretched. Direct linear transformation enables three-dimensional reconstructions of peripheral nerve length during stretch to measure strain. Currently, no methodology exists to study the in-situ strain of stretched peripheral nerves using a stereo-imaging camera system calibrated via direct linear transformation. Capturing the in-situ strain of peripheral nerves when stretched can not only aid clinicians in understanding underlying injury mechanisms of nerve damage when overstretched but also help optimize treatment strategies that rely on stretch-induced interventions. The methodology described in the paper has the potential to enhance our understanding of peripheral nerve biomechanics in response to stretch to improve patient outcomes in the field of nerve injury management and rehabilitation.

At present, peripheral nerve injuries (PNIs) are one of the leading causes of substantial impairment around the globe. Complete recovery of nerve function after an injury is challenging. Currently, autologous nerve grafts are being used as a treatment; however, this has several downsides, for example, donor site morbidity, shortage of donor sites, loss of sensation, inflammation, and neuroma development. The most promising alternative is the development of a nerve guide conduit (NGC) to direct the restoration and renewal of neuronal axons from the proximal to the distal end to facilitate nerve regeneration and maximize sensory and functional recovery. Alternatively, the response of nerve cells to electrical stimulation (ES) has a substantial regenerative effect. The incorporation of electrically conductive biomaterials in the fabrication of smart NGCs facilitates the function of ES throughout the active proliferation state. This article overviews the potency of the various categories of electroactive smart biomaterials, including conductive and piezoelectric nanomaterials, piezoelectric polymers, and organic conductive polymers that researchers have employed latterly to fabricate smart NGCs and their potentiality in future clinical application. It also summarizes a comprehensive analysis of the recent research and advancements in the application of ES in the field of NGC., (© 2023 The Authors. Journal of Biomedical Materials Research Part A published by Wiley Periodicals LLC.)

Background: Neuropathies are commonplace in clinical practice and ultrasound assessment of the peripheral nerves is increasingly becoming a valuable diagnostic tool to support the physical and electrophysiological examinations. In the pertinent literature, several sonographic approaches have been proposed to evaluate the peripheral nerve tissue-mainly based on (semi)-quantitative measures., Objective: To define a standardized sonographic approach aiming to evaluate the different sono-histological sections of the peripheral nerve also in a qualitative way., Methods: Using high-frequency ultrasound probes and high-level ultrasound machines, we matched the histopathological features of the peripheral nerve (in acute and chronic phase) and the different sonographic patterns. Moreover, high-sensitive power Doppler assessments have been performed to assess the microcirculation of the peripheral nerve in physiological and pathological conditions., Results: Modern ultrasound equipment allows a "real-time dissection" of the peripheral nerve evaluating the sonographic patterns of its different histological compartments in physiological and pathological conditions. Moreover, high-sensitive power Doppler allows clear visualization of the microcirculation of the peripheral nerve both in the acute and chronic phases of the neuropathy., Conclusion: In clinical practice, using adequate technological equipment, (semi)-quantitative measurements of the peripheral nerve can be coupled with different sonographic patterns of its histological components-both in the acute and chronic phase of the peripheral neuropathy. This way, better/prompt diagnosis and optimal management of the patients would be possible., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate and line the endoneurial tubes to guide and support regenerating axons. The axons emerge from the stump of the viable nerve attached to the neuronal soma. The SCs downregulate myelin-associated genes and concurrently, upregulate growth-associated genes that include neurotrophic factors as do the injured neurons. However, the gene expression is transient and progressively fails to support axon regeneration within the SC-containing endoneurial tubes. Moreover, despite some preference of regenerating motor and sensory axons to "find" their appropriate pathways, the axons fail to enter their original endoneurial tubes and to reinnervate original target organs, obstacles to functional recovery that confront nerve surgeons. Several surgical manipulations in clinical use, including nerve and tendon transfers, the potential for brief low-frequency electrical stimulation proximal to nerve repair, and local FK506 application to accelerate axon outgrowth, are encouraging as is the continuing research to elucidate the molecular basis of nerve regeneration.

Background: Millions of Americans experience residual deficits from traumatic peripheral nerve injury (PNI). Despite advancements in surgical technique, repair typically results in poor functional outcomes due to prolonged periods of denervation resulting from long regenerative distances coupled with slow rates of axonal regeneration. Novel surgical solutions require valid preclinical models that adequately replicate the key challenges of clinical PNI., Objective: To develop a preclinical model of PNI in swine that addresses 2 challenging, clinically relevant PNI scenarios: long segmental defects (≥5 cm) and ultra-long regenerative distances (20-27 cm). Thus, we aim to demonstrate that a porcine model of major PNI is suitable as a potential framework to evaluate novel regenerative strategies prior to clinical deployment., Methods: A 5-cm-long common peroneal nerve or deep peroneal nerve injury was repaired using a saphenous nerve or sural nerve autograft, respectively. Histological and electrophysiological assessments were performed at 9 to 12 mo post repair to evaluate nerve regeneration and functional recovery. Relevant anatomy, surgical approach, and functional/histological outcomes were characterized for both repair techniques., Results: Axons regenerated across the repair zone and were identified in the distal stump. Electrophysiological recordings confirmed these findings and suggested regenerating axons reinnervated target muscles., Conclusion: The models presented herein provide opportunities to investigate peripheral nerve regeneration using different nerves tailored for specific mechanisms of interest, such as nerve modality (motor, sensory, and mixed fiber composition), injury length (short/long gap), and total regenerative distance (proximal/distal injury)., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Objective: To assess the indications for and utility of diagnostic ultrasonography (US) in a series of consecutive patients with suspected traumatic peripheral nerve lesions (TPNL)., Methods: We retrospectively reviewed the electronic medical records of consecutive patients referred from February 2013 to May 2018 to our US laboratory. All included patients were examined using standard US equipment, with a 4-13MHz linear array transducer., Results: In the analyzed period, we performed US examinations in 143 patients with 149 suspected TPNL. Electrodiagnostically (EDx) complete TPNL were found in 63 (45%), partial in 59 (42%), and only demyelination (i.e., neurapraxia) in four (3%) patients. TPNL could not be confirmed in 14 (10%) patients. Nerve discontinuity was not demonstrated by US in any of the patients with EDx incomplete nerve lesions. Contact of the nerve with osteosynthetic material (OSM) was found in eight of 33 patients (24%). In five patients, the nerve could not be adequately evaluated throughout its course due to extensive changes in the surrounding tissues., Discussion: In acute situations, US is most useful in EDx complete TPNL to differentiate between nerve axonotmesis and neurotmesis. High-velocity trauma, lacerations, and bone fractures are all risk factors for neurotmesis. In chronic situations, US is useful in cases of functionally inefficient reinnervation, neuropathic pain, or progressive nerve dysfunction. In such patients, the surrounding tissues and the relation of the nerve to any OSM need to be carefully examined. US examination is probably not needed in patients with TPNL following acute blunt trauma, only minor clinical deficits and/or slightly/moderately abnormal EDx findings., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Objective: To review the literature on the research status of vascularization of tissue engineered peripheral nerve so as to provide the theoretical basis for the vascularization of tissue engineered peripheral nerve., Methods: The literature related to the vascularization of peripheral nerve tissue engineering in recent years was reviewed and summarized according to the five aspects of promoting vascularization: local microenvironment and blood supply characteristics of peripheral nerve regeneration, scaffold material modification, seed cells, autologous vascular bundle implantation, and pro-vascular factors., Results: Tissue engineered peripheral nerve has brought a new hope for the repair of peripheral nerve injury, but the repair effect of large nerve defects is not good, which is mainly related to the degree of vascularization of the nerve grafts. So it is particularly important to promote the early vascularization of tissue engineered peripheral nerve. Previous studies have mainly focused on the four aspects of scaffold material modification, seed cells, autologous vascular bundle implantation, and angiogenesis related factors. Recent studies show that the combination of the above two or more factors in the tissue engineered peripheral nerves can better promote the vascularization of tissue engineered peripheral nerves., Conclusion: Promoting early vascularization of tissue engineered peripheral nerves can provide timely nutritional support for seed cells on the scaffold, promote axon growth and nerve regeneration, and facilitate the repair of large peripheral nerve defects in clinical practice.

Artificial and non-artificial nerve grafts are the gold standard in peripheral nerve reconstruction in cases with extensive loss of nerve tissue, particularly where a direct end-to-end suture or an autologous nerve graft is inauspicious. Different materials are marketed and approved by the US Food and Drug Administration (FDA) for peripheral nerve graft reconstruction. The most frequently used materials are collagen and poly(DL-lactide-ε-caprolactone). Only one human nerve allograft is listed for peripheral nerve reconstruction by the FDA. All marketed nerve grafts are able to demonstrate sufficient nerve regeneration over small distances not exceeding 3.0 cm. A key question in the field is whether nerve reconstruction on large defect lengths extending 4.0 cm or more is possible. This review gives a summary of current clinical and experimental approaches in peripheral nerve surgery using artificial and non-artificial nerve grafts in short and long distance nerve defects. Strategies to extend nerve graft lengths for long nerve defects, such as enhancing axonal regeneration, include the additional application of Schwann cells, mesenchymal stem cells or supporting co-factors like growth factors on defect sizes between 4.0 and 8.0 cm.

Recent anatomical discoveries indicate the importance of identifying membranes and compartments surrounding peripheral nerves into which local anesthetic agents can be injected and continuous nerve block catheters placed during regional anesthetic procedures. However, current markers used in anatomical studies have multiple drawbacks, specifically extravasation into noninjected locations, which can result in inadequate treatment. We studied a readily-available new marker, heparinized blood solution (HBS), which is easy to identify by microscopy and can remain in the nerve compartment into which it is deposited without distorting the tissue. We collected blood from 22 patients and prepared it as HBS. This was then injected into four fresh cadavers as in routine clinical practice for ultrasound-guided nerve blocks to form a so-called "doughnut" by "hydro-dissecting" at 32 sites. All samples, including nerves and neighboring tissues, were then prepared and examined by light microscopy. Although no deliberate intraneural injection was attempted, the marker was identified inside all the nerve compartments except the fascicles. Apart from leaking through the needle entry site in some instances, there was no extravasation of the HBS into neighboring nerve compartments in either direction. The tissues were not distorted and the erythrocytes did not form a thrombus. Nerve membranes and compartments could be clearly identified with routine staining. This technique enabled us to study the longitudinal and circumferential spread in all nerve compartments and to collect data for better interpretation of factors influencing an anesthetic nerve block and situations in which complications could possibly arise. HBS seemed superior to other markers because it did not leave the compartments into which it had been injected, did not distort the tissue, and was easily visible under the light microscope. Clin. Anat., 31:1050-1057, 2018. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Nerve guidance conduits (NGCs) have been drawing considerable attention as an aid to promote regeneration of injured axons across damaged peripheral nerves. Ideally, NGCs should include physical and topographic axon guidance cues embedded as part of their composition. Over the past decades, much progress has been made in the development of NGCs that promote directional axonal regrowth so as to repair severed nerves. This paper briefly reviews the recent designs and fabrication techniques of NGCs for peripheral nerve regeneration. Studies associated with versatile design and preparation of NGCs fabricated with either conventional or rapid prototyping (RP) techniques have been examined and reviewed. The effect of topographic features of the filler material as well as porous structure of NGCs on axonal regeneration has also been examined from the previous studies. While such strategies as macroscale channels, lumen size, groove geometry, use of hydrogel/matrix, and unidirectional freeze-dried surface are seen to promote nerve regeneration, shortcomings such as axonal dispersion and wrong target reinnervation still remain unsolved. On this basis, future research directions are identified and discussed., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Modern technologies enable deep tissue focusing of nanosecond pulsed electric field (nsPEF) for non-invasive nerve and muscle stimulation. However, it is not known if PEF orders of magnitude shorter than the activation time of voltage-gated sodium channels (VGSC) would evoke action potentials (APs). One plausible scenario requires the loss of membrane integrity (electroporation) and resulting depolarization as an intermediate step. We report, for the first time, that the excitation of a peripheral nerve can be accomplished by 12-ns PEF without electroporation. 12-ns stimuli at 4.1-11 kV (3.3-8.8 kV/cm) evoked APs similarly to conventional stimuli (100-250 μs, 1-5 V, 103-515 V/m), except for having higher selectivity for the faster nerve fibers. Nerves sustained repeated tetanic stimulations (50 Hz or 100 Hz for 1 min) alternately by 12-ns PEF and by conventional pulses. Such tetani caused a modest AP decrease, to a similar extent for both types of stimuli. Nerve refractory properties were not affected. The lack of cumulative damages even from tens of thousands of 12-ns stimuli and the similarities with the conventional stimulation prove VGSC activation by nsPEF without nerve membrane damage.

Peripheral nerve injuries have produced major concerns in regenerative medicine for several years, as the recovery of normal nerve function continues to be a significant clinical challenge. Chitosan (CHT), because of its good biocompatibility, biodegradability and physicochemical properties, has been widely used as a biomaterial in tissue engineering scaffolding. In this study, CHT membranes were produced with three different Degrees of Acetylation (DA), envisioning its application in peripheral nerve regeneration. The three CHT membranes (DA I: 1%, DA II: 2%, DA III: 5%) were extensively characterized and were found to have a smooth and flat surface, with DA III membrane having slightly higher roughness and surface energy. All the membranes presented suitable mechanical properties and did not show any signs of calcification after SBF test. Biodegradability was similar for all samples, and adequate to physically support neurite outgrowth. The in vitro cell culture results indicate selective cell adhesion. The CHT membranes favoured Schwann cells invasion and proliferation, with a display of appropriate cytoskeletal morphology. At the same time they presented low fibroblast infiltration. This fact may be greatly beneficial for the prevention of fibrotic tissue formation, a common phenomenon impairing peripheral nerve regeneration. The great deal of results obtained during this work permitted to select the formulation with the greatest potential for further biological tests., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Restoration of normal neurological function of transected peripheral nerve challenged regenerative medicine and surgery. Previous studies showed that Nectin-like molecule 1 (NECL1) is one of the important adhesion molecules on the axons and Schwann cells is located along the internodes in direct apposition to NECL1. In this study, we fabricated PLGA membrane pre-coated with NECL1, mimicking the natural axons to enhance the adhesion of Schwann cells. Investigation of the cellular response in vitro was performed by detecting cytotoxicity, proliferation, morphology, viability, specific markers and Scanning Electron Microscopy (SEM) of Schwann cells cultured in PLGA. Further, the NECL1-coated PLGA conduits were used for peripheral nerve repair after sciatic nerve defect was constructed. Results showed that PLGA-coated NECL1 enhanced cell proliferation compared with PLGA, as evidenced by MTT analysis, cell viability assay and histological evaluation. RT-PCR results showed that GDNF (glial cell line-derived neurotrophic factor), BDNF (brain-derived neurotrophic factor), CNTF (ciliary neurotrophic factor) and neurotrophic factors of axonal regeneration were highly expressed in PLGA/NECL1 group. S100, which is Schwann cell marker, was also elevated in PLGA-NCEL1 in both mRNA and protein expression as demonstrated by PCR and immunohistochemical examination. Moreover, in vivo study showed that implantation of PLGA/NCEL1 tubes in bridging the nerve defect can significantly improve Schwann cell aggregation and attachment and greatly enhance the functional recovery of nerve regeneration as compared with control and PLGA groups. Therefore, the novel blend of PLGA/NECL1 conduits proved to be promising candidate for tissue engineering scaffold., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Functional PNS regeneration requires injured axons to return to their original synaptic targets, yet the mechanisms underlying target-selective regeneration have remained elusive. Using live-cell imaging in zebrafish we find that regenerating motor axons exhibit a strong preference for their original muscle territory and that axons probe both correct and incorrect trajectories extensively before selecting their original path. We show that this process requires the glycosyltransferase lh3 and that post-injury expression of lh3 in Schwann cells is sufficient to restore target-selective regeneration. Moreover, we demonstrate that Schwann cells neighboring the transection site express the lh3 substrate collagen4a5 and that during regeneration collagen4a5 destabilizes axons probing inappropriate trajectories to ensure target-selective regeneration, possibly through the axonal repellant slit1a. Our results demonstrate that selective ECM components match subpopulations of regenerating axons with their original targets and reveal a previously unappreciated mechanism that conveys synaptic target selection to regenerating axons in vivo. VIDEO ABSTRACT., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Positioning-related injuries caused during surgery under anesthesia are most likely multifactorial. Pathologic mechanical forces alone (overstretching and/or ischemia from direct compression) may not fully explain postsurgical neuropathy with recent evidence implicating patient-specific factors or perioperative inflammatory responses spatially and even temporally divorced from the anatomical region of injury. The aim of this introductory article is to provide an overview of anatomic considerations of these mechanical forces on soft and nervous tissues along with factors that may compound compression or stretch injury. Three subsequent articles will address specific positioning-related anatomic considerations of the (1) upper extremities, (2) lower extremities, and (3) central nervous system and soft tissues., (© 2015 Wiley Periodicals, Inc.)

Peripheral nerve injuries are common conditions, with broad-ranging groups of symptoms depending on the severity and nerves involved. Although much knowledge exists on the mechanisms of injury and regeneration, reliable treatments that ensure full functional recovery are scarce. This review aims to summarize various ways these injuries are classified in light of decades of research on peripheral nerve injury and regeneration., (Copyright © 2013. Published by Elsevier Inc.)

Introduction: The cavernous nerve (CN) is commonly injured during prostatectomy. Manipulation of the nerve microenvironment is critical to improve regeneration and develop novel erectile dysfunction therapies. Sonic hedgehog (SHH) treatment promotes CN regeneration. The mechanism of how this occurs is unknown. Brain-derived neurotrophic factor (BDNF) facilitates return of erectile function after CN injury and it has been suggested in cortical neurons and the sciatic nerve that BDNF may be a target of SHH., Aim: To determine if SHH promotes CN regeneration through a BDNF-dependent mechanism., Methods: Sprague Dawley rats underwent (i) bilateral CN crush (N = 15); (ii) SHH treatment of pelvic ganglia (PG)/CN (N = 10); (iii) SHH inhibition in PG/CN (N = 14 rats); (iv) CN crush with SHH treatment of PG/CN (N = 10 rats); (v) CN crush with SHH treatment and BDNF inhibition (N = 14 rats); and (vi) CN injury and SHH treatment of the penis (N = 23)., Main Outcome Measures: BDNF and glial fibrillary acidic protein were quantified in PG/CN by Western, and a t-test was used to determine differences., Results: In normal rats SHH inhibition in the PG/CN decreased BDNF 34% and SHH treatment increased BDNF 36%. BDNF was increased 44% in response to SHH treatment of crushed CNs, and inhibition of BDNF in crushed CNs treated with SHH protein hampers regeneration., Conclusions: SHH regulates BDNF in the normal and regenerating PG/CN. BDNF is part of the mechanism of how SHH promotes regeneration, thus providing an opportunity to further manipulate the nerve microenvironment with combination therapy to enhance regeneration., (© 2012 International Society for Sexual Medicine.)

Chimpanzee attacks can be vicious, mutilating, and disabling if not fatal. Stereotypically, the hands and face are targeted, and in male victims, genitalia are mutilated. The authors present a case highlighting the difficulties with early neurological assessment following such an attack. This 55-year-old woman was attacked by a 14-year-old chimpanzee. She suffered mutilation of both hands, severe midface bony, soft-tissue, and eye injuries, and scalp degloving. An emergency tracheotomy was performed at the scene, with an unclear duration of hypoxia. The patient was unresponsive without spontaneous movements, papillary or corneal reflexes, cough, or gag. Attempts to lighten sedation were not tolerated. Brain CTs were normal. Intracranial pressure monitoring was deemed infeasible. Brain MR imaging suggested diffuse axonal injury consistent with severe shaking trauma. Diffusion tensor imaging indicated intact corticospinal tracts, confirmed by somatosensory evoked potentials. Magnetic resonance imaging suggested left optic nerve transaction, and right retinal detachment was diagnosed. Electroencephalography showed severe diffuse encephalopathy. Auditory evoked potentials showed absent auditory pathway responses except for a right delayed wave V. Visual evoked potentials indicated absent visual function. At 1 month after the attack, sedation and analgesia weaning revealed lower-extremity movement to command, but no upper-limb response. Cervical spine and brachial plexus MR imaging showed brachial plexus edema. Two months after the attack, the patient regained strength in all her extremities and verbally communicated using a Passy-Muir tracheostomy valve. Chimpanzee attacks on humans can cause extensive, life-threatening injuries. The neurological assessment of such patients is challenging, complicated by limb and craniofacial disfigurement and the need for heavy sedation. Initial assessment of nervous system integrity may rely on costly imaging and electrophysiological studies.

Peripheral nerve injury is a common casualty and although peripheral nerve fibers retain a considerable regeneration potential also in the adult, recovery is usually rather poor, especially in case of large nerve defects. The aim of this paper is to address the perspectives in regeneration and tissue engineering after peripheral nerve injury by reviewing the relevant experimental studies in animal models. After a brief overview of the morphological changes related to peripheral nerve injury and regeneration, the paper will address the evolution of peripheral nerve tissue engineering with special focus on transplantation strategies, from organs and tissues to cells and genes, that can be carried out, particularly in case of severe nerve lesions with substance loss. Finally, the need for integrated research which goes beyond therapeutic strategies based on single approaches is emphasized, and the importance of bringing together the various complimentary disciplines which can contribute to the definition of effective new strategies for regenerating the injured peripheral nerve is outlined., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Insufficient recovery after peripheral nerve injury has been attributed to (i) poor pathfinding of regrowing axons, (ii) excessive collateral axonal branching at the lesion site and (iii) polyneuronal innervation of the neuromuscular junctions (NMJ). The facial nerve transection model has been used initially to measure restoration of function after varying therapies and to examine the mechanisms underlying their effects. Since it is very difficult to control the navigation of several thousand axons, efforts concentrated on collateral branching and NMJ-polyinnervation. Treatment with antibodies against trophic factors to combat branching improved the precision of reinnervation, but had no positive effects on functional recovery. This suggested that polyneuronal reinnervation--rather than collateral branching--may be the critical limiting factor. The former could be reduced by pharmacological agents known to perturb microtubule assembly and was followed by recovery of function. Because muscle polyinnervation is activity-dependent and can be manipulated, attempts to design a clinically feasible therapy were performed by electrical stimulation or by soft tissue massage. Electrical stimulation applied to the transected facial nerve or to paralysed facial muscles did not improve vibrissal motor performance and failed to diminish polyinnervation. In contrast, gentle stroking of the paralysed muscles (vibrissal, orbicularis oculi, tongue musculature) resulted in full recovery of function. This manual stimulation was also effective after hypoglossal-facial nerve suture and after interpositional nerve grafting, but not after surgical reconstruction of the median nerve. All these findings raise hopes that clinically feasible and effective therapies could be soon designed and tested., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Peripheral nerve injuries result in loss of motor, sensory and autonomic functions of the denervated limb, but are also accompanied by positive symptoms, such as hyperreflexia, hyperalgesia and pain. Strategies to improve functional recovery after neural injuries have to address the enhancement of axonal regeneration and target reinnervation and also the modulation of the abnormal plasticity of neuronal circuits. By enhancing sensory inputs and/or motor outputs, activity-dependent therapies, like electrostimulation or exercise, have been shown to positively influence neuromuscular functional recovery and to modulate the plastic central changes after experimental nerve injuries. However, it is important to take into account that the type of treatment, the intensity and duration of the protocol, and the period during which it is applied after the injury are factors that determine beneficial or detrimental effects on functional recovery. The adequate maintenance of activity of neural circuits and denervated muscles results in increased trophic factor release to act on regenerating axons and on central plastic changes. Among the different neurotrophins, BDNF seems a key player in the beneficial effects of activity-dependent therapies after nerve injuries., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Animal models of nerve compression, crush, and transection injuries of peripheral nerves have been subject to extensive study in order to understand the mechanisms of injury and axon regeneration and to investigate methods to promote axon regeneration and improve functional outcomes following nerve injury. Six outcome measures of regenerative success including axon and neuron counts, muscle and motor unit contractile forces, and behavior are reviewed in the context of nerve injury types, crush, transection and nerve repair by direct coaptation, or transection and repair via a nerve graft or conduit. The measures are evaluated for sciatic, tibial, common peroneal, femoral, single nerve branches such as the soleus nerve, and facial nerves. Their validity is discussed in the context of study objectives and the nerve branch. The case is made that outcome measures of axon counts and muscle contractile forces may be valid during the early phases of axon regeneration when regenerating sprouts emerge asynchronously from the proximal nerve stump and regenerate towards their denervated targets. However, care must be taken especially when experimental interventions differentially affect how many neurons regenerate axons and the number of axons per neuron that sprout from the proximal nerve stumps. Examples of erroneous conclusions are given to illustrate the need for researchers to ensure that the appropriate outcome measures are used in the evaluation of the success of peripheral nerve regeneration., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Full functional recovery after traumatic peripheral nerve injury is rare. We postulate three reasons for the poor functional outcome measures observed. Axon regeneration is slow and not all axons participate. Significant misdirection of regenerating axons to reinnervate inappropriate targets occurs. Seemingly permanent changes in neural circuitry in the central nervous system are found to accompany axotomy of peripheral axons. Exercise in the form of modest daily treadmill training impacts all three of these areas. Compared to untrained controls, regenerating axons elongate considerably farther in treadmill trained animals and do so via an autocrine/paracrine neurotrophin signaling pathway. This enhancement of axon regeneration takes place without an increase in the amount of misdirection of regenerating axons found without training. The enhancement also occurs in a sex-dependent manner. Slow continuous training is effective only in males, while more intense interval training is effective only in females. In treadmill trained, but not untrained mice the extent of coverage of axotomized motoneurons is maintained, thus preserving important elements of the spinal circuitry., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Wallerian degeneration is a cascade of stereotypical events in reaction to injury of nerve fibres. These events consist of cellular and molecular alterations, including macrophage invasion, activation of Schwann cells, as well as neurotrophin and cytokine upregulation. This review focuses on cellular and molecular changes distal to various types of peripheral nerve injury which simultaneously contribute to axonal regeneration and neuropathic pain induction. In addition to the stereotypical events of Wallerian degeneration, various types of nerve damage provide different conditions for both axonal regeneration and neuropathic pain induction. Wallerian degeneration of injured peripheral nerve is associated with an inflammatory response including rapid upregulation of the immune signal molecules like cytokines, chemokines and transcription factors with both beneficial and detrimental effects on nerve regeneration or neuropathic pain induction. A better understanding of the molecular interactions between the immune system and peripheral nerve injury would open the possibility for targeting these inflammatory mediators in therapeutic interventions. Understanding the pleiotropic effects of cytokines/chemokines, however, requires investigating their highly specific pathways and precise points of action., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

The authors report their 10-year experience in the treatment of war injuries in the Gaza strip. Bullet injuries to nerves can be assessed using Sunderland's classification. Grade 4 and 5 lesions must be repaired in the same way as any traumatic nerve injuries. A detailed series of sciatic nerve repair is presented. In this series, 12 nerve gaps were repaired by direct nerve coaptation using 90° knee flexion for six weeks. The results of this technique at 1 to 4 years follow-up are better than to those of sciatic nerve grafting., (Copyright © 2011. Published by Elsevier SAS.)

Although autologous nerve graft is still the first choice strategy in nerve reconstruction, it has the severe disadvantage of the sacrifice of a functional nerve. Cell transplantation in a bioartificial conduit is an alternative strategy to improve nerve regeneration. Nerve fibrin conduits were seeded with various cell types: primary Schwann cells (SC), SC-like differentiated bone marrow-derived mesenchymal stem cells (dMSC), SC-like differentiated adipose-derived stem cells (dASC). Two further control groups were fibrin conduits without cells and autografts. Conduits were used to bridge a 1 cm rat sciatic nerve gap in a long term experiment (16 weeks). Functional and morphological properties of regenerated nerves were investigated. A reduction in muscle atrophy was observed in the autograft and in all cell-seeded groups, when compared with the empty fibrin conduits. SC showed significant improvement in axon myelination and average fiber diameter of the regenerated nerves. dASC were the most effective cell population in terms of improvement of axonal and fiber diameter, evoked potentials at the level of the gastrocnemius muscle and regeneration of motoneurons, similar to the autografts. Given these results and other advantages of adipose derived stem cells such as ease of harvest and relative abundance, dASC could be a clinically translatable route towards new methods to enhance peripheral nerve repair., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Purpose: The gold standard for the treatment of segmental nerve defect is an autogenous nerve graft. However, donor site morbidity is an inevitable complication. We substituted an autogenous nerve graft with an inside-out vein graft for the treatment of segmental sensory nerve defect and the clinical results were evaluated retrospectively., Patients and Methods: Eleven patients of sensory nerve defects have undertaken inside-out vein grafts for the recovery of sensation. The involved nerves were digital nerves in three cases, peroneal nerves in two cases, saphenous nerve in two cases, and superficial radial nerves in four cases. The average length of defects was 2.71 cm (1-6 cm). Donor veins were harvested 4 mm longer than nerve defects and everted to promote nerve regeneration. Patients' objective satisfactions and two-point discriminations were determined, the Semmes-Weinstein monofilament test was performed, and British Medical Council sensory functional scores were evaluated., Results: Sensory functional scores recovered to over S3 in all cases. No donor site morbidity was caused by vein harvesting, and all patients achieved satisfactory results with protective sensation at involved sites., Conclusion: The inside-out vein graft offers a good surgical alternative to an autogenous nerve graft for the reconstruction of sensory nerve defects without donor site morbidity., (Copyright © 2011 Wiley-Liss, Inc.)

Purpose: The optimal management of a nerve gap within the fingers remains an unanswered question in hand surgery. The purpose of this study was to compare the sensory recovery, cost, and complication profile of digital nerve repair using autogenous vein and polyglycolic acid conduits., Methods: We enrolled patients undergoing repair of digital nerve injuries with gaps precluding primary repair. The minimum gap that was found to preclude primary repair was 4 mm. Each nerve repair was randomized to the type of nerve repair with either a woven polyglycolic acid conduit or autogenous vein. Time required for repair was recorded. We performed sensory testing, consisting of static and moving 2-point discrimination, at 6 and 12 months after repair. We compared patient factors between the 2 groups using chi-square and Student's t-test. We compared sensory recovery between the 2 groups at each time point using Student's t-test and compared time and cost of repair., Results: We enrolled 42 patients with 76 nerve repairs. Of these, 37 patients (representing 68 repairs) underwent sensory evaluation at the 6-month time point. The median age in this group was 35 years. We repaired 36 nerves with synthetic conduit and 32 with vein. Nerve gaps ranged from 4 to 25 mm (mean, 10 mm). Study groups were not significantly different regarding age, time to repair, gap length, medical history, smoking history, or worker's compensation status. Time to harvest the vein was longer but the average cost of materials and surgery in the vein group was $1,220, compared with $1,269 for synthetic conduit repairs. These differences were not statistically significant. Mean static and moving 2-point discrimination at 6 months for the synthetic conduit group were 8.3 ± 2.0 and 6.6 ± 2.3, respectively, compared with 8.5 ± 1.8 and 7.1 ± 2.2 for the vein group. Values at 12 months for the synthetic conduit group were 7.5 ± 1.9 and 5.6 ± 2.2, compared with 7.6 ± 2.6 and 6.6 ± 2.9 for the vein group. These differences were not statistically significant. Smokers and worker's compensation patients had a worse sensory recovery at 12 months postrepair. There were 2 extrusions in the synthetic conduit group requiring reoperation; however, the difference in extrusion rate was not found to be statistically significant., Conclusions: Sensory recovery after digital nerve reconstruction with autogenous vein conduit was equivalent to that using polyglycolic acid conduit, with a similar cost profile and fewer postoperative complications., (Copyright © 2011 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

The objective of the present neurohistological study using an experimental model of compressive-ischemic neuropathy (40 white rats) was to estimate the influence of photochromotherapy on the injured nerve filament. It was shown that light of different wavelengths had differential effect on the nerve tissue. The exposure to blue light reduced the severity of traumatic lesion as apparent from a decrease in the number of filaments undergoing degenerative changes and their enhanced argentophilia. Irradiation with red light caused a marked decrease in the degree of vacuolization with moderate argentophilia suggesting normalization of ion transport and recovery of nerve conductivity. Green light irradiation promoted remyelinization of nerve filaments (a marked increase of the number of Schwann cells).

Objectives: To investigate the types of traumatic peripheral nerve injuries by ultrasound (US). To demonstrate the efficacy of US in case of peripheral nerve injuries and, in particular, its importance of demonstrating and monitoring the appearances of the nerve itself., Methods: Two hundred and two patients, of which 117 subsequently underwent operative treatment, were prospectively examined by US in such a way that the transducer was moved to the nerve damaged region from the normal nerve located near a known anatomical landmark. The ultrasound features of the traumatic peripheral nerve injuries were classified according to abnormal fascicle, perineurium, epineurium, and peripheral tissues of peripheral nerve., Results: The ultrasound features of the traumatic peripheral nerve injuries were classified into 7 types. In the 117 cases that underwent operative treatment, the accuracy of classification by using US was 93.2%., Conclusions: Ultrasound seems to be a valuable investigation for evaluating the type of traumatic peripheral nerve injury.

The aim of this study was to evaluate the long-term effect of localized growth factor delivery on sciatic nerve regeneration in a critical-size (> 1 cm) peripheral nerve defect. Previous work has demonstrated that bioactive proteins can be encapsulated within double-walled, poly(lactic-co-glycolic acid)/poly(lactide) microspheres and embedded within walls of biodegradable polymer nerve guides composed of poly(caprolactone). Within this study, nerve guides containing glial cell line-derived neurotrophic factor (GDNF) were used to bridge a 1.5-cm defect in the male Lewis rat for a 16-week period. Nerve repair was evaluated through functional assessment of joint angle range of motion using video gait kinematics, gastrocnemius twitch force, and gastrocnemius wet weight. Histological evaluation of nerve repair included assessment of Schwann cell and neurofilament location with immunohistochemistry, evaluation of tissue integration and organization throughout the lumen of the regenerated nerve with Masson's trichrome stain, and quantification of axon fiber density and g-ratio. Results from this study showed that the measured gastrocnemius twitch force in animals treated with GDNF was significantly higher than negative controls and was not significantly different from the isograft-positive control group. Histological assessment of explanted conduits after 16 weeks showed improved tissue integration within GDNF releasing nerve guides compared to negative controls. Nerve fibers were present across the entire length of GDNF releasing guides, whereas nerve fibers were not detectable beyond the middle region of negative control guides. Therefore, our results support the use of GDNF for improved functional recovery above negative controls following large axonal defects in the peripheral nervous system.

Sensory neurons express a variety of voltage-gated Ca2+ channel subtypes, but reports differ on their proportionate representation, and the effects of painful nerve injury on each subtype are not established. We compared levels of high-voltage activated currents in medium-sized (30-40 μm) dorsal root ganglion neurons dissociated from control animals and those subjected to spinal nerve ligation, using sequential application of semiselective channel blockers (nisoldipine for L-type, SNX-111 or ω-conotoxin GVIA for N-type, agatoxin IVA or ω-conotoxin MVIIC for P/Q-type, and SNX-482 for a component of R-type) during either square wave depolarizations or action potential waveform voltage commands. Using sequential administration of multiple blockers, proportions of total Ca2+ current attributable to different subtypes and the effect of injury depended on the sequence of blocker administration and type of depolarization command. Overall, however, N-type and L-type currents comprised the dominant components of ICa in sensory neurons under control conditions, and these subtypes showed the greatest loss of current following injury (L-type 26-71% loss, N-type 0-51% loss). Further exploration of N-type current identified by its sensitivity to ω-conotoxin GVIA applied alone showed that injury reduced the peak N-type current during step depolarization by 68% and decreased the total charge entry during action potential waveform stimulation by 44%. Isolation of N-type current by blockade of all other subtypes demonstrated a 50% loss with injury, and also revealed an injury-related rightward shift in the activation curve. Non-stationary noise analyses of N-type current in injured neurons revealed unitary channel current and number of channels that were not different from control, which indicates that injury-induced loss of current is due to a decrease in channel open probability. Our findings suggest that diminished Ca2+ influx through N-type and L-type channels may contribute to sensory neuron dysfunction and pain after nerve injury., (Published by Elsevier Ltd.)

Pulsed magnetic fields (PMFs) have well-known beneficial effects on nerve regeneration. However, little research has examined the nerve conduction characteristics of regenerating peripheral nerves under PMF. The main goal of this study was to examine the conduction characteristics of regenerating peripheral nerves under PMFs. The sucrose-gap recording technique was used to examine the conduction properties of injured sciatic nerves of rats exposed to PMF. Following the injury, peripheral nerves were very sensitive to repetitive stimulation. When the stimulation frequency was increased, the amplitude of the compound action potential (CAP) decreased more at 15 days post-crush injury (dpc) than at 38 dpc. PMF treatment for 38 days after injury caused significant differences in the conduction of CAPs. Moreover, application of PMF ameliorated the abnormal electrophysiological activities of nerves such as hyperpolarizing afterpotentials and delayed depolarizations that were revealed by 4-aminopyridine (4-AP). Consequently, characteristic findings in impulse conduction of recovered nerves under PMF indicate that the observed abnormalities in signaling or aberrant ion channel functions following injury may be restored by PMF application., (Copyright © 2010 Wiley-Liss, Inc.)

This study aims to estimate the effects of using one donor nerve to repair the injured nerve and itself simultaneously by biodegradable chitin conduit. Proximal median nerve served as donor nerve to repair the distal median and whole ulnar nerve. Four months postoperation, the number of myelinated axons and nerve conduction velocities of the distal median and ulnar nerve were (2085 ± 215 and 24.4 ± 5.9 m/s), and (1193 ± 102 and 30.7 ± 11.2 m/s). Recovery of the tetanic muscle forces of the reinvervated muscles were also observed. It suggests that Dor to Dor+Rec neurorrhaphy is a practical method for severe peripheral nerve injury.

The infraorbital branch of the trigeminal nerve (ION) is essential in whisker-specific neural patterning ("barrelettes") in the principal nucleus of the trigeminal nerve (PrV). The barrelettes are formed by the ION terminal arbors, somata, and dendrites of the PrV cells; they are abolished after neonatal damage to the ION. Physiological studies show that disruption of the barrelettes is accompanied by conversion of functional synapses into silent synapses in the PrV. In this study, we used whole cell recordings with a paired-pulse stimulation protocol and MK-801 blocking rate to estimate the presynaptic release probability (Pr) of ION central trigeminal afferent terminals in the PrV. We investigated Pr during postnatal development, following neonatal ION damage, and determined whether conversion of functional synapses into silent synapses after peripheral denervation results from changes in Pr. The paired-pulse ratio (PPR) was quite variable ranging from 40% (paired-pulse depression) to 175% (paired-pulse facilitation). The results from paired-pulse protocol were confirmed by MK-801 blocking rate experiments. The nonuniform PPRs did not show target cell specificity and developmental regulation. The distribution of PPRs fit nicely to Gaussian function with a peak at ∼ 100%. In addition, neonatal ION transections did not alter the distribution pattern of PPR in their central terminals, suggesting that the conversion from functional synapses into silent synapses in the peripherally denervated PrV is not caused by changes in the Pr.

Studies of mice deficient in classical major histocompatability complex class I (MHCI) revealed that MHCI plays an important role in neurodevelopment in the central nervous system. We previously studied the effects of recombinant MHCI molecules on wildtype retina explants and observed that MHCI can inhibit retina neurite outgrowth, with self-MHCI molecules having greater inhibitory effect than non-self MHCI molecules. Here, we examined classical MHCI's effects on axon outgrowth from neurons of the peripheral nervous system (PNS). We used the embryonic dorsal root ganglia (DRG) explant model since their neurons express MHCI and because DRG explants have been widely used to assess the effects of molecules on axonal outgrowth from PNS neurons. We observed that picomolar levels of a recombinant self-MHCI molecule, but not non-self MHCI molecules, inhibited axon outgrowth from DRG explants. This differential sensitivity to self- vs. non-self MHCI suggests that early in development, self-MHCI may "educate" PNS neurons to express appropriate MHCI receptors, as occurs during natural killer cell development. Furthermore, we observed that a MHCI tetramer stained embryonic DRG neurons, indicating the expression of classical MHCI receptors. These results suggest that MHCI and MHCI receptors play roles during early stages of PNS development and may provide new targets of therapeutic strategies to promote neuronal outgrowth after PNS injury., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Peripheral nerve injury leads to changes in the proximal axon. Traumatic nerve injuries in humans were investigated to characterize such electrophysiological changes. Mixed nerve conduction studies (MNCS) and motor conduction studies (MCS) were performed proximal to the injury. Control values were obtained from the uninjured limb. Median (n = 24) and ulnar (n = 35) nerve injuries were studied. The injured nerves had significant mixed nerve action potential (MNAP) amplitude reductions (median: P < 0.0001; ulnar: P < 0.0001). The majority of the MNAP amplitude reductions were severe and early. There was slowing in the mixed nerve conduction velocity (MNCV) (median: P = 0.09; ulnar: P = 0.04) and motor conduction velocity (MCV) (median: P = 0.046; ulnar: P = 0.005). Axonal loss appears to play a significant role in producing the MNCS changes observed, and its early occurrence is noteworthy. Proximal MCV reduction could be secondary to the effects of injury as well as collateral sprouting of uninjured axons. Proximal axonal changes may have an impact on recovery., (Copyright © 2011 Wiley Periodicals, Inc.)

Objective: To study the characteristics of forensic identification cases involved with peripheral nerve injury, and to discuss how to apply the clinical information, forensic examination and neurophysiological testing., Methods: One hundred and fifty-eight cases which were diagnosed peripheral nerve injury in clinic, were collected. Then the individual characteristics, injuries, identification results, exaggeration or camouflage were analysed., Results: The male, the unemployed, and the young and middle-aged were common in our cases. The main reasons of "peripheral nerve injury" were traffic accidents and sharp injuries. Most wounded parts were in limbs. Also the exaggeration and camouflage accounted for a considerable proportion in our cases., Conclusion: The forensic identification of "peripheral nerve injury" cases should be evaluated with clinical information, forensic examination and electrophysiological testing comprehensively.

Object: Surgical treatment of nerve lesions in continuity remains difficult, even in the most experienced hands. The regenerative potential of those injuries can be evaluated by intraoperative electrophysiological studies and/or intraneural dissection. The present study examines the value of intraoperative high-frequency ultrasound as an imaging tool for decision making in the management of traumatic nerve lesions in continuity., Methods: Intraoperative high-frequency ultrasound was applied to 19 traumatic or iatrogenic nerve lesions of differing extents. The information obtained was correlated with intraoperative electrophysiological, microsurgical intraneural dissection, and histopathological findings in resected nerve segments., Results: The intraoperative application of high-resolution, high-frequency ultrasound enabled morphological examination of nerve lesions in continuity, with good image quality. The assessment of the severity of the underlying nerve injury matched perfectly with the judgment obtained from intraoperative electrophysiological studies. Both intraneural nerve dissection and neuropathological examination of the resected nerve segments confirmed the sonographic findings. In addition, intraoperative ultrasound proved to be very time efficient., Conclusions: With intraoperative ultrasound, the extent of traumatic peripheral nerve lesions can be examined morphologically for the first time. It is a promising, noninvasive method that seems capable of assessing the type (intraneural/perineural) and grade of nerve fibrosis. Therefore, in combination with intraoperative neurophysiological studies, intraoperative high-resolution ultrasound may represent a major tool for noninvasive assessment of the regenerative potential of a nerve lesion.

The MRL/MpJ mouse displays an accelerated ability to heal ear punch wounds without scar formation (whereas wounds on the dorsal surface of the trunk heal with scar formation), offering a rare opportunity for studying tissue regeneration in adult mammals. A blastema-like structure develops and subsequently the structure of the wounded ear is restored, including cartilage, skin, hair follicles and adipose tissue. We sought to assess if the MRL/MpJ strain also possessed an enhanced capacity for peripheral nerve regeneration. Female MRL/MpJ and C57BL/6 mice were wounded with a 2-mm excisional biopsy punch to the centre of each ear and two 4-mm excisional biopsy punches to the dorsal skin. Immunohistochemical dual staining of pan-neurofilament and CD31 markers was used to investigate reinnervation and vascularisation of both the dorsal surface of the trunk and ear wounds. The MRL/MpJ mouse ear exhibited a significantly (P > 0.01) higher density of regenerated nerves than C57BL/6 between 10 and 21 days post-wounding when the blastema-like structure was forming. Unlike dorsal skin wounds, nerve regeneration in the ear wound preceded vascularisation, recapitulating early mammalian development. Immunohistochemical data suggest that factors within the blastemal mesenchyme, such as aggrecan, may direct nerve regrowth in the regenerating ear tissue., (© 2010 The Authors. Journal of Anatomy © 2010 Anatomical Society of Great Britain and Ireland.)